Hypoxic cells that are found in solid
tumors are resistant to anticancer drugs and
radiation therapy. Thus, for effective anticancer
chemotherapy, it is important to identify drugs with selective toxicity towards hypoxic cells. The recent development of new drugs that are toxic only when activated in the hypoxic cell opens a new era of
cancer treatment. Recently, we evaluated the
hypoxia-selective toxicity of four differently substituted
quinoxaline 1,4-dioxides (QdNOs) in human
cancer cells. These compounds were synthesized by the Beirut Reaction. The various QdNOs were found to exert potent hypoxic cytotoxic activities against human
colon cancer cells (T-84) and to possess a 50-100 fold greater cytotoxicity under
hypoxia compared to oxia. Interestingly, the
hypoxia cytotoxicity ratio (HCR: ratio between
drug concentration in air and in
hypoxia to give 10% cell survival) of these compounds was found to depend on the nature of the substituents on the
quinoxaline 1,4-dioxide heterocycle. Because of their differential hypoxic cytotoxicity, these drugs could provide useful therapeutic agents against solid
tumors. Presently we are investigating the selective cytotoxicity of QdNOs for hypoxic cells in
tumors in vivo and their ability to potentiate radiation-induced
tumor cell killing. We will also study their in vitro anti-angiogenic activity and their mechanism of action at the molecular level. The deciphering of the mechanism of action of QdNOs may allow us to ultimately recommend their use as therapeutic agents against human
tumors.